Results of a phase IIa study of VX-809, an investigational CFTR corrector compound, in subjects with cystic fibrosis homozygous for the F508del-CFTR mutation
John P. Clancy,Steven M. Rowe,Frank J. Accurso,Moira L. Aitken,Raouf S. Amin,Melissa A. Ashlock,Manfred Ballmann,Michael P. Boyle,Inez Bronsveld,Preston W. Campbell,Kris De Boeck,Scott H. Donaldson,Henry L. Dorkin,Jordan M. Dunitz,Peter R. Durie,Manu Jain,Anissa Leonard,Karen McCoy,Richard B. Moss,Joseph M. Pilewski,Daniel B. Rosenbluth,Ronald C. Rubenstein,Michael S. Schechter,Martyn Botfield,Claudia L. Ordoñez,George T. Spencer-Green,Laurent Vernillet,Steve Wisseh,Karl Yen,Michael W. Konstan +29 more
TLDR
In this study, VX-809 had a similar adverse event profile to placebo for 28 days in F508del-CFTR homozygous patients, and demonstrated biological activity with positive impact on CFTR function in the sweat gland.Abstract:
BACKGROUND: VX-809, a cystic fibrosis transmembrane conductance regulator (CFTR) modulator, has been shown to increase the cell surface density of functional F508del-CFTR in vitro. METHODS: A randomised, double-blind, placebo-controlled study evaluated the safety, tolerability and pharmacodynamics of VX-809 in adult patients with cystic fibrosis (n=89) who were homozygous for the F508del-CFTR mutation. Subjects were randomised to one of four VX-809 28 day dose groups (25, 50, 100 and 200 mg) or matching placebo. RESULTS: The type and incidence of adverse events were similar among VX-809- and placebo-treated subjects. Respiratory events were the most commonly reported and led to discontinuation by one subject in each active treatment arm. Pharmacokinetic data supported a once-daily oral dosing regimen. Pharmacodynamic data suggested that VX-809 improved CFTR function in at least one organ (sweat gland). VX-809 reduced elevated sweat chloride values in a dose-dependent manner (p=0.0013) that was statistically significant in the 100 and 200 mg dose groups. There was no statistically significant improvement in CFTR function in the nasal epithelium as measured by nasal potential difference, nor were there statistically significant changes in lung function or patient-reported outcomes. No maturation of immature F508del-CFTR was detected in the subgroup that provided rectal biopsy specimens. CONCLUSIONS: In this study, VX-809 had a similar adverse event profile to placebo for 28 days in F508del-CFTR homozygous patients, and demonstrated biological activity with positive impact on CFTR function in the sweat gland. Additional data are needed to determine how improvements detected in CFTR function secondary to VX-809 in the sweat gland relate to those measurable in the respiratory tract and to long-term measures of clinical benefit. CLINICAL TRIAL NUMBER: NCT00865904.read more
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Journal ArticleDOI
Lumacaftor–Ivacaftor in Patients with Cystic Fibrosis Homozygous for Phe508del CFTR
Jennifer L. Taylor-Cousar,Anne Munck,Edward F. McKone,Cornelis K. van der Ent,Alexander Moeller,Christopher Simard,Linda T Wang,Edward P. Ingenito,Charlotte M. McKee,Yimeng Lu,J Lekstrom-Himes,J. Stuart Elborn +11 more
TL;DR: These data show that lumacaftor in combination with ivacaftors provided a benefit for patients with cystic fibrosis homozygous for the Phe508del CFTR mutation.
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Correction of the F508del-CFTR protein processing defect in vitro by the investigational drug VX-809
Fredrick Van Goor,Sabine Hadida,Peter D. J. Grootenhuis,B. Burton,Jeffrey H. Stack,Kimberly Straley,Caroline Decker,Mark R. Miller,Mccartney Jason,Eric R. Olson,Jeffrey J. Wine,Raymond A. Frizzell,Melissa A. Ashlock,Paul A. Negulescu +13 more
TL;DR: F508del-CFTR corrected by VX-809 exhibited biochemical and functional characteristics similar to normal CFTR, including biochemical susceptibility to proteolysis, residence time in the plasma membrane, and single-channel open probability.
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A functional CFTR assay using primary cystic fibrosis intestinal organoids
Johanna F. Dekkers,Caroline L. Wiegerinck,Hugo R. de Jonge,Inez Bronsveld,Hettie M. Janssens,Karin M. de Winter-de Groot,Arianne M. Brandsma,Nienke W M de Jong,Marcel J. C. Bijvelds,Bob J. Scholte,Edward E. S. Nieuwenhuis,Stieneke van den Brink,Hans Clevers,Cornelis K. van der Ent,Sabine Middendorp,Jeffrey M. Beekman +15 more
TL;DR: This relatively simple and robust assay will facilitate diagnosis, functional studies, drug development and personalized medicine approaches in cystic fibrosis.
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Cystic fibrosis genetics: from molecular understanding to clinical application
TL;DR: Recent progress in elucidating disease mechanism and causes of phenotypic variation, as well as in the development of treatments, demonstrates that genetics continues to play an important part in cystic fibrosis research 25 years after the discovery of the disease-causing gene.
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Cystic fibrosis: a mucosal immunodeficiency syndrome.
Taylor S. Cohen,Alice S. Prince +1 more
TL;DR: The development of animal models that approximate the human pulmonary phenotypes—airway inflammation and spontaneous infection—may provide the much-needed tools to establish how CFTR regulates mucosal immunity and to test directly the effect of pharmacologic potentiation and correction of mutant CFTR function on bacterial clearance.
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